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Antiproteinuric effect of the cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease T Fujita1, K Ando1, H Nishimura2, T Ideura3, G Yasuda4, M Isshiki1 and K Takahashi1 on behalf of the Cilnidipine versus Randomized Trial for Evaluation in Renal Disease (CARTER) Study Investigators

1Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 2Division of Internal Medicine, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan; 3Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan and 4Division of Nephrology, Yokohama City University Medical Center, Yokohama, Japan

Cilnidipine, a dual L-/N-type calcium channel blocker, dilates Based on the accumulating data from a large number of both efferent and afferent and is renoprotective. clinical mega-trials,1–5 it has been established that an Our multi-center, open-labeled, and randomized trial inhibitor of the renin–angiotensin system (RAS), such as an compared the antiproteinuric effect of cilnidipine with that angiotensin-converting enzyme (ACE) inhibitor and an of amlodipine in hypertensive patients with disease. angiotensin II type 1 receptor blocker (ARB), has an apparent A group of 339 patients, already receiving renin–angiotensin renoprotective effect. Although the guidelines for the system inhibitor treatment, were randomly assigned to management of hypertension6–8 recommend that blood cilnidipine or amlodipine. The primary endpoint was a pressure (BP) should be strictly controlled in hypertensive decrease in the urinary protein to creatinine ratio. After patients with kidney disease, adequate BP levels are seldom 1-year of treatment, systolic and diastolic blood pressures achieved with only one RAS inhibitor. Actually, combination of were significantly reduced in both groups which did not two to three antihypertensive drugs is required to decrease BP differ between them. The urinary protein to creatinine ratio to target levels, especially in patients with kidney disease.9 One significantly decreased in the cilnidipine compared to the of the main candidates for a combination with an RAS inhibitor amlodipine group. Cilnidipine exerted a greater is a dihydropyridine-type calcium channel blocker (CCB), antiproteinuric effect than amlodipine even in the subgroup because it reduces BP even in patients who are sometimes whose fell below the target level. This study considered relatively resistant to antihypertensive drugs.10 suggests that cilnidipine is superior to amlodipine in However, evidence for the renoprotective effect of preventing the progression of proteinuria in hypertensive dihydropyridine CCBs is inconsistent. For example, ramipril patients when coupled with a renin–angiotensin system had a greater renoprotective effect compared with amlodi- inhibitor. pine in the African American Study of Kidney Disease and 4 Kidney International (2007) 72, 1543–1549; doi:10.1038/sj.ki.5002623; (AASK) study. Moreover, the risk of a published online 17 October 2007 doubling of the serum creatinine (Cr) was similar between KEYWORDS: L-/N-type calcium channel blocker; L-type calcium channel amlodipine and placebo groups in the Irbesartan Diabetic blocker; proteinuria; kidney disease; hypertension Nephropathy Trial (IDNT).11 In a recent meta-analysis, the mean change in urinary protein was approximately þ 2% for dihydropyridine CCBs.12 On the other hand, the antiprotei- nuric effect of cilnidipine has been shown in several types of hypertensive animal models13,14 and hypertensive patients with kidney disease.15,16 The addition of a dihydropyridine CCB to treatment with an RAS inhibitor is also associated with inconsistent renal effects. The Blood-pressure Control for Renoprotection in Patients with Non-diabetic Chronic Renal Disease Trial (REIN-2) group showed that the addition Correspondence: T Fujita, Department of Nephrology and Endocrinology, of was not of further renal benefit in patients with University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, non-diabetic proteinuric nephropathies and background of 17 Tokyo 113-8655, Japan. E-mail: [email protected] ramipril therapy. On the other hand, cilnidipine further Received 28 May 2007; revised 3 August 2007; accepted 14 August reduced urinary albumin in patients with type II diabetic 18 2007; published online 17 October 2007 nephropathy under treatment with valsartan.

Kidney International (2007) 72, 1543–1549 1543 original article T Fujita et al.: Antiproteinuric effect of cilnidipine

This inconsistency may be due to the different specificity group: diuretic n ¼ 14, a-blocker n ¼ 4, b-blocker n ¼ 1). for calcium channels of each dihydropyridine CCB;19 there During treatment, 32 subjects from the cilnidipine group are several variants of calcium channels, such as L, N, T, P/Q, (adverse reaction: n ¼ 9, cardiovascular event: n ¼ 1, death: and R.20,21 Actually, cilnidipine, an L-/N-type dihydro- n ¼ 2, lost to follow-up: n ¼ 20 (discontinuation: n ¼ 13, pyridine CCB, was shown to suppress renal injury in moving away: n ¼ 4, protocol violation: n ¼ 3)) and 30 hypertensive animals and humans13–16 but amlodipine4,11 subjects from the amlodipine group (adverse reaction: and felodipine,17 an L-type CCBs, were not. Cilnidipine had a n ¼ 13, cardiovascular event: n ¼ 4, death: n ¼ 3, lost to greater renoprotective effect than amlodipine in rat14 and follow-up: n ¼ 10 (discontinuation: n ¼ 8, moving away: small-size clinical studies.16 The blockade of N-type calcium n ¼ 2)) withdrew from the study. channels is able to inhibit renal sympathetic nerve activity14 and the resulting efferent arteriolar vasodilation protected the Changes in BP and rate glomeruli through the attenuation of glomerular hyperten- Systolic BP was slightly but significantly (Po0.05) greater at sion.13 However, because L-type calcium channels do not 2 months of treatment in the amlodipine group than in the express in glomerular efferent arterioles,22 the renoprotective cilnidipine group but did not differ at the other time points effects of an L-type CCB are expected to be lower than those of an L-/N-type CCB. There is still a lack of clinical trials comparing the renoprotective effects of an L-/N-type and L- Table 1 | Baseline characteristics type CCBs added to treatment with an RAS inhibitor, which Variable Cilnidipine Amlodipine P-value is frequently prescribed for hypertensive disease in clinical n 179 160 practice. Thus, we compared the antiproteinuric effects of Age (years) 59.9713.3 59.3712.9 NS cilnidipine with those of amlodipine in hypertensive patients Sex (male/female) 121/58 93/67 NS with kidney disease who were already under treatment with an RAS inhibitor. Causative disease Diabetic nephropathy 70 59 Primary renal disease 57 61 RESULTS Hypertensive 34 26 NS Study population nephrosclerosis g Three hundred and fifty subjects were enrolled for this study Others 18 14 and of them 11 were excluded based on the selection criteria BP (Figure 1). Thus, 339 subjects (these were 90.2% of required Systolic BP (mm Hg) 152.4714.8 152.4714.8 NS sample size with our estimation) were randomly allocated to Diastolic BP (mm Hg) 86.979.6 88.079.4 NS the cilnidipine group (n ¼ 179) or amlodipine group Heart rates (beats per min) 76712 74710 NS (n ¼ 160). The baseline characteristics of the subjects in the Body mass index (kg mÀ2) 24.673.7 24.874.1 NS two groups are shown in Table 1 and baseline medication is Urinary protein/Cr ratio 192172126 171271572 NS shown in Table 2. There were no significant differences (mg gÀ1) Serum Cr (mg dlÀ1) 1.2770.58 1.2970.60 NS between the two groups. The final dose was 7 7 7 À1 Serum total 210 44 218 43 NS 11.5 5.6 mg day in the cilnidipine group and (mg dlÀ1) À1 5.372.4 mg day in the amlodipine group. Twenty subjects Serum HDL cholesterol 56720 55716 NS from the cilnidipine group and 17 from the amlodipine (mg dlÀ1) 7 7 group were added antihypertensive drugs other than a CCB Serum triglycerides 169 183 182 112 NS (mg dlÀ1) or an RAS inhibitor during the treatment (cilnidipine group: Diabetes mellitus 81 (45%) 67 (42%) NS diuretic n ¼ 12, a-blocker n ¼ 5, b-blocker n ¼ 5; amlodipine Cerebrovascular disease 11 (6%) 7 (4%) NS Ischemic heart disease 9 (5%) 9 (6%) NS BP, blood pressure, Cr, creatinine, HDL, high-density lipoprotein; NS, not significant. 350 assessed for eligibility

11 excluded as ineligible Table 2 | Baseline medication 339 randomized Medication Cilnidipine Amlodipine P-value

179 cilnidipine 160 amlodipine RAS inhibitor ARB 114 98 32 discontinued study drug 30 discontinued study drug ACE inhibitor 41 45 NS 9 adverse reaction g 13 adverse reaction ARB+ACE inhibitor 24 17 1 cardiovascular events 4 cardiovascular events Diuretics 45 45 NS 2 died 3 died 20 lost to follow-up 10 lost to follow-up b-Blocker 16 17 NS a-Blocker 17 16 NS Central agent 1 1 NS 147 completed study 130 completed study ACE, angiotensin-converting enzyme; ARB, angiotensin II type 1 blocker; NS, not Figure 1 | Flow of participants throughout the study. significant; RAS, renin-angiotensin system.

1544 Kidney International (2007) 72, 1543–1549 T Fujita et al.: Antiproteinuric effect of cilnidipine original article

(Figure 2). Diastolic BP did not differ between the two but not in the amlodipine group ( þ 13.977.7%: s.e.m.), groups during the treatment. In the last month of treatment, showing a significant (Po0.01) difference between the two systolic (cilnidipine; 133.1715.6 mm Hg, amlodipine; groups. Even in subgroups with different baseline, urinary 134.5716.6 mm Hg, NS) and diastolic (75.678.7 vs protein/Cr ratio, age, sex, or BP after the 12 months of 77.979.4 mm Hg, NS) BP did not differ either. Subjects treatment, cilnidipine significantly suppressed the urinary with a BP o140/90 mm Hg accounted for 69.3 and 62.3% in protein/Cr ratio compared with amlodipine (Figure 4). In a the cilnidipine and amlodipine groups (NS), respectively. subgroup with primary renal disease, cilnidipine was also Subjects with a BP o130/85 mm Hg accounted for 36.9 and more antiproteinuric than amlodipine. In a subgroup with 37.7% (NS), respectively; BP level of this subgroup was also diabetic nephropathy, although the percent changes in similar between cilnidipine and amlodipine groups (systolic urinary protein/Cr ratio did not differ between the two BP: 120.576.8 vs 118.976.5 mm Hg, diastolic BP: 71.377.7 groups (Figure 4), its absolute value was lower in the vs 73.276.1 mm Hg, NS, respectively). Heart rate did not cilnidipine group than in the amlodipine group differ either (cilnidipine; 73.9711.8 beats per min, amlodi- (1160.57171.6 vs 2405.07447.1 mg gÀ1: s.e.m., Po0.05) pine; 73.6711.7 beats per min, NS). after 1 year of treatment, while the baseline urinary protein/ Cr ratio did not differ (2243.37330.4 vs 2137.57 Changes in urinary protein/Cr ratio 268.3 mg gÀ1: s.e.m., NS). However, in the subgroup with In the cilnidipine group, the urinary protein/Cr ratio was hypertensive nephrosclerosis, the antiproteinuric effect was significantly lower in the last month of the study than in the amlodipine group (1308.67121.2 vs 1881.17188.8 mg gÀ1: s.e.m., Po0.05) (Figure 3). When the percent change from baseline was calculated, it was significantly lower in the Subgroup n Changes in urinary protein P-value Cilnidipine Amlodipine cilnidipine group at 3 months of treatment or later. After 12 Baseline urinary protein/Cr ratio 201 <0.05 –1 months of treatment, the urinary protein/Cr ratio had >1500 mg g 129 <0.05 decreased in the cilnidipine group (À14.475.6%: s.e.m.) Age 132 <0.05 <65 year-old 198 <0.05 Sex Male 208 Systolic BP Amlodipine <0.05 180 Cilnidipine Female 122 * <0.05 160 BP after 12-month treatment <130/85 mm Hg 123 <0.05 140 207 <0.05 120 NS 100 Diabetic nephropathy 129 Primary renal disease 118 <0.001 80 Hypertensive nephrosclerosis 60 NS

60 –50 –40 –30 –20 –100 1020304050 Blood pressure (mm Hg) Diastolic BP 40 Pre 3 6 9 12 months Figure 4 | Changes in urinary protein/Cr ratio in subgroups with different baseline urinary protein/Cr ratio, age, sex, BP Figure 2 | Changes in systolic and diastolic BP. BP was almost after 12 months of treatment, or etiology of kidney disease. the same in the cilnidipine (closed circles) and the amlodipine Results are expressed as the mean7s.e.m. The antiproteinuric effect (open circles) groups except for a slight difference in systolic BP at was superior in the cilnidipine group compared with the amlodipine one point. *Po0.05, cilnidipine vs amlodipine groups. group even in the different subgroups.

2500 20 †† 15 2000 10 5 1500 0 –5 1000 Percentage –10

500 –15 –20

Urinary protein (mg per g creatinine) 0 –25 Pre 1 3 6 12 months 1 3 6 12 months

Amlodipine 160 147 142 137 130 Amlodipine Cilnidipine Cilnidipine 179 168 168 160 146 Figure 3 | Changes in urinary protein/Cr ratio during the treatment period. Results are expressed as the mean7s.e.m. The urinary w protein/Cr ratio was suppressed in the cilnidipine group but not in the amlodipine group. *Po0.05, Po0.01, cilnidipine vs amlodipine groups.

Kidney International (2007) 72, 1543–1549 1545 original article T Fujita et al.: Antiproteinuric effect of cilnidipine

not different between cilnidipine and amlodipine, probably and in four treated with amlodipine (general malaise, pleural due to the small number of subjects (n ¼ 60, totally). effusion, lung cancer, and carcinomatous peritonitis).

Changes in serum Cr DISCUSSION The serum Cr was slightly increased in both groups, but after In this study, we firstly demonstrated that cilnidipine was 1 year of treatment, the level was similar in the two groups more beneficial than amlodipine as additional medication for (1.3770.72 vs 1.4570.83 mg dlÀ1). hypertensive patients who had kidney disease associated with significant proteinuria (urinary protein/Cr ratio Cardiovascular events and death X300 mg gÀ1) and who were under treatment with an RAS The occurrence of cardiovascular disease was two times inhibitor. Our results further confirm those of previous greater in the amlodipine group but the difference between reports showing that cilnidipine had greater antiproteinuric the two groups was not statistically significant (Table 3). effects than amlodipine,14,16 and those of a study showing There was no case of cardiovascular death in the cilnidipine that the combination therapy with cilnidipine and an ARB group, while two subjects died in the amlodipine group ameliorated urinary albumin more potently than (sudden death and rupture of aortic aneurysm), but the ARB monotherapy.18 In this study, moreover, cilnidipine was difference was not significant. The all cause mortality rate did more beneficial than amlodipine even under treatment of an not significantly differ. RAS inhibitor. As a dihydropyridine CCB is frequently prescribed as secondary choice for patients with hypertensive Adverse reactions disease treated with an RAS inhibitor, the present results Adverse reactions were observed in 20 subjects of the should have an impact on the practical management of cilnidipine group and in 19 patients of the amlodipine hypertension associated with kidney disease; it is suggested group (Table 4). About half of the adverse reactions in each that cilnidipine, a dual L-/N-type CCB, rather than an L-type group (cilnidipine n ¼ 10, amlodipine n ¼ 10) were consid- CCB should be recommended to be ‘second agents’ in ered to relate to the study drugs. Severe adverse reactions hypertensive patients with significant proteinuria under were observed in two subjects treated with cilnidipine treatment with an RAS inhibitor. (exacerbation of renal failure and metastatic lung cancer) In addition to RAS inhibition, strict BP control is considered to play an important role in preventing the Table 3 | Cardiovascular events and death progression of kidney disease.6–8 In this study, although Cilnidipine Amlodipine systolic and diastolic BPs did not differ as a whole, slight lower systolic BP levels were observed in cilnidipine group at Cardiovascular disease 13 Angina pectoris 1 0 2 month of the treatment. However, this insubstantial Myocardial infarction 0 1 difference of systolic BP for the short-time period may not Abdominal aortic rupture 0 1 affect urinary protein. Also, in the previous report,23 24 h Sudden death 0 1 ambulatory BP measurement showed no significant differ- Stroke 24ence in the reduction in any of the BP parameters between Cerebral infarction 2 3 cilnidipine and amlodipine, associated with similar decrease Transient ischemic attack 0 1 in office BP. In this study, required BP goal was not attended as a whole. However, even in subjects whose BP was All cause mortality 23 Cardiovascular death 0 2 controlled at o130/85 mm Hg, the antiproteinuric effect of Non-cardiovascular death 2 1 cilnidipine was greater compared with that of amlodipine (Figure 4) despite the comparable BP reduction in both groups, suggesting that the beneficial effect of cilnidipine may Table 4 | Adverse reactions be beyond its BP lowering effect. Therefore, even if the target Cilnidipine Amlodipine BP is achieved, the choice of an appropriate secondary dihydropyridine CCB might be critical for hypertensive Hypotension 0 2 Palpitation 3 0 patients with kidney disease under treatment with an RAS Edema 2 1 inhibitor. Hot flushes 0 1 The greater antiproteinuric effect attained with cilnidipine Headache 0 1 compared with amlodipine may be due to the N-type Malaise, fatigue 1 1 Skin reaction 2 1 calcium channel blockade achieved with cilnidipine, but not Abnormal laboratory data 6 0 with amlodipine, and the resultant sympathetic nerve Worsening of function 3 1 inhibition.14 Supporting this hypothesis, non-hypotensive Worsening of kidney function 2 1 doses of moxonidine, an agent that reduces sympathetic Others 9 12 Total number of patientsa 20 19 nerve activity, could ameliorate not only albuminuria but 24 aFive patients with cilnidipine and one patient with amlodipine had two or more also structural damage in subtotally nephrectomized rats, adverse reactions. suggesting a potential role of the increased sympathetic nerve

1546 Kidney International (2007) 72, 1543–1549 T Fujita et al.: Antiproteinuric effect of cilnidipine original article

activity in progression of renal failure. There is a consistent urinary protein/Cr ratio in spot urine collection is well intimate relationship between the sympathetic nervous correlated with daily urinary protein excretion.35–38 Actually, system and urinary protein excretion in patients with chronic systematic review by Price et al.39 suggested that the protein/ kidney disease.25 For example, moxonidine reduced urinary Cr ratio on a random urine specimen could be useful in albumin in patients with .26 A number clinical practice. Also, the Work Group of the Kidney Disease of relatively small clinical studies have suggested that non- Outcomes Quality Initiative of the National Kidney Founda- dihydropyridine CCBs, which attenuated sympathetic nerve tion recommended first morning urine collection or random activity, reduce urinary protein more markedly than spot urine collection to monitor proteinuria in patients with dihydropyridine CCBs, which do not exert a sympatho- established kidney disease.40 Actually, in clinical practice, 24 h inhibitory effect, although both types of CCBs similarly urine collection cannot be often accepted by patients with decrease BP.27,28 Accordingly, cilnidipine, a dual L-/N-type mild to moderate kidney disease. Therefore, urinary protein/ CCB, has been reported to have a greater renoprotective Cr ratio from spot urine collection may be a parameter to effect than amlodipine, an L-type CCB,14,16 which is meet clinical practice, although there are some limitations in compatible with the result of this study. These findings are spot urine collection. supported by experimental studies indicating that cilnidi- Sample size and period of treatment are an additional pine-induced N-type calcium channel blockade inhibits renal limitation of our study. Although the cardiovascular risks of sympathetic nerve activity,14 inducing a reduction of patients were mild to moderate, the number of patients was glomerular hypertension through a vasodilation of efferent relatively small (n ¼ 339, totally) and this study was short arterioles,13 but that an L-type CCB does not effectively (1 year). Thus, cardiovascular events were too rare and the reduce glomerular hypertension because of the absence of L- changes in serum Cr were too slight to sufficiently evaluate type calcium channels in the efferent arterioles.22 Taken the influence of cilnidipine. Actually, the occurrence of together, these results strongly support the hypothesis that cardiovascular events and death in the cilnidipine group was the antiproteinuric effect of cilnidipine might be account for approximately half that of the amlodipine group, but the the inhibition of sympathetic nerve activity through the difference was not statistically significant. Also, the changes in blockade of N-type calcium channels in chronic kidney serum Cr were not significantly different between the two disease patients with the increased sympathetic activity.25,26 groups. Small sample size, moreover, causes a limitation of On the other hand, an L-type CCB may rather cause subgroup analysis such as diabetic nephropathy and hyper- sympathoactivation through a direct vasodilator effect. tensive glomerulosclerosis (Figure 4). In addition, diagnosis Several clinical studies demonstrate that proteinuria is a of cardiovascular event depended on judgment of individual predictor of subsequent progression of kidney disease; for investigators, which was also a limitation on evaluation of example, in multivariate analysis of data from the AASK cardiovascular events in this study. study,29 baseline proteinuria correlated to decline of glomer- In conclusion, the addition of cilnidipine rather than ular filtration ratio independently. Importantly, proteinuria amlodipine ameliorated urinary protein excretion in hyper- has been recently recognized to be one of cardiovascular risk tensive patients with kidney disease who were already under factors. In the Framingham cohort, proteinuria showed a treatment with an RAS inhibitor. Therefore, combination three-fold increase of the mortality rate and was strongly therapy with cilnidipine and an RAS inhibitor may be associated with other risk factors for cardiovascular disease.30 recommended for these patients. In a sub-analysis in the Systolic Hypertension in Europe (Syst-Eur) trial,31 proteinuria was a significant predictor of MATERIALS AND METHODS total mortality and all cardiovascular end points. Experi- Participants mental and clinical data converge to indicate that, in chronic This study was a multicenter, open-labeled, randomized trial kidney disease, proteinuria reduction protects against renal conducted in 35 hospitals (Appendix) in Japan from June 2002 to 32 and cardiovascular failure. Fosinopril, which decreased July 2006. This study was approved by the Institutional Review urinary albumin excretion, exhibited much greater reduction Board of The University of Tokyo Clinical Research Center and by of cardiovascular events during the 4-year follow-up than the review board of all the other hospitals, and it was undertaken in calculated reduction using Framingham risk score, but accordance with the Declaration of Helsinki Principles. Written pravastatin, which did not affect urinary albumin, inhibited informed consent was obtained from all subjects. The enrollment cardiovascular events comparably to calculated reduction.33 criteria of the subjects included (1) urinary protein/Cr ratio X300 mg gÀ1 (average of two consecutive measurements during a Thus, antiproteinuric antihypertensive drugs are considered À1 to be more beneficial regarding the cardiovascular as well as 4-week period before the treatment), (2) serum Crp3.0 mg dl , (3) systolic and diastolic BPX130/85 mm Hg, and (4) treatment with an renal outcome in patients with kidney disease. ARB or an ACE inhibitor during 2–3 months or more before the In this study, 24-h urine collection could not be carried administration of cilnidipine or amlodipine. The exclusion criteria out, because it may be too inconvenient and cumbersome for were (1) age younger than 20 years or older than 80 years; (2) outpatients to give their cooperation to this study. Although hypertensive emergency; (3) severe , severe arrhythmia, 24 h urine collection is a gold standard that is suggested to be angina, and myocardial infarction within 6 months of the start of a best practice,34 several investigators demonstrated that the trial; (4) stroke within 6 months of the start of the trial; (5)

Kidney International (2007) 72, 1543–1549 1547 original article T Fujita et al.: Antiproteinuric effect of cilnidipine

severe diabetes mellitus, which required hospitalization because of 5. Ruggenenti P, Perna A, Gherardi G et al. Renoprotective properties of extremely high plasma or complications such as diabetic ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354: 359–364. ketoacidosis; (6) pregnancy; and (7) history of severe side effects of a 6. Mancia G, De Backer G, Dominiczak A et al. 2007 Guidelines for the CCB, an ARB or an ACE inhibitor. Required sample size was management of arterial hypertension: the task force for the management estimated as 376 that significant difference could be detected when of arterial hypertension of the European society of hypertension (ESH) the difference of both groups was 10% (statistical power: 80%, two- and of the European society of cardiology (ESC). J Hypertens 2007; 25: 15 1105–1187. sided level of significance: 5%) considering the previous report. 7. Chobanian AV, Bakris GL, Black HR et al. 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